Emerging strategies for exploiting cannabinoid receptor agonists as medicines

Medicines that activate cannabinoid CB₁ and CB₂ receptor are already in the clinic. These are Cesamet® (nabilone), Marinol® (dronabinol; Δ⁹-tetrahydrocannabinol) and Sativex® (Δ⁹-tetrahydrocannabinol with cannabidiol). The first two of these medicines can be prescribed to reduce chemotherapy-induced nausea and vomiting. Marinol® can also be prescribed to stimulate appetite, while Sativex® is prescribed for the symptomatic relief of neuropathic pain in adults with multiple sclerosis and as an adjunctive analgesic treatment for adult patients with advanced cancer. One challenge now is to identify additional therapeutic targets for cannabinoid receptor agonists, and a number of potential clinical applications for such agonists are mentioned in this review. A second challenge is to develop strategies that will improve the efficacy and/or the benefit-to-risk ratio of a cannabinoid receptor agonist. This review focuses on five strategies that have the potential to meet either or both of these objectives. These are strategies that involve: (i) targeting cannabinoid receptors located outside the blood-brain barrier; (ii) targeting cannabinoid receptors expressed by a particular tissue; (iii) targeting up-regulated cannabinoid receptors; (iv) targeting cannabinoid CB₂ receptors; or (v) ‘multi-targeting’. Preclinical data that justify additional research directed at evaluating the clinical importance of each of these strategies are also discussed.